A Antagonist, , Reduces Cue-Induced Cocaine Craving in Cocaine-Dependent Subjects Malcolm S. Reid, Ph.D., Joanne D. Mickalian, M.S., Kevin L. Delucchi, Ph.D., and S. Paul Berger, M.D.

We have previously shown that nicotine enhances cue- cue measures. Cue exposure also produced an increase in induced cocaine craving. In the present study, the effects of skin conductance and decrease in skin temperature. The a nicotine antagonist, mecamylamine, on cue-induced cue-induced increase in cocaine craving was reduced, cocaine craving were investigated. Twenty-three cocaine- while the cue-induced skin conductance and temperature dependent patients, all cigarette smokers, were randomly responses were unaffected, by mecamylamine. These assigned to mecamylamine (2.5 mg tablet) or placebo in a findings show that cue-induced cocaine craving is single-dose, placebo-controlled, crossover, double-blind attenuated by mecamylamine. Further study on the use study. Craving and anxiety were measured before and after of mecamylamine in relapse prevention programs cocaine cues with visual analog scales for desire to use are suggested. cocaine and mood. Skin conductance, skin temperature and [Neuropsychopharmacology 20:297–307, 1999] heart rate were recorded before and during cocaine cues. © 1999 American College of Neuropsychopharmacology. Following exposure to cocaine cues, all patients reported an Published by Elsevier Science Inc. increase in cocaine craving and anxiety relative to the pre-

KEY WORDS: Cocaine; Craving; Mecamylamine; Nicotine; and cocaine paraphernalia handling (Ehrman et al. 1992; Reid et al. 1998). The cocaine cue procedure ap- pears to be contextually specific because opiate-related Over the past several years, numerous studies have cues are less effective whereas cues specific to the sub- demonstrated that environmental cues previously asso- ject’s mode of cocaine use are most effective (Ehrman et ciated with cocaine use will consistently induce cocaine al. 1992; O’Brien et al. 1990, 1992). Furthermore, cocaine craving in cocaine-dependent subjects (Ehrman et al. cue reactivity persists inpatients who have not used co- 1992; O’Brien et al. 1990; Berger et al. 1996; Reid et al. caine for several months (Rohsenow et al. 1991; O’Brien 1998). This behavior is readily elicited in a clinical labo- et al. 1990). In recent years, this model has been used to ratory setting by means of a standardized cocaine cue investigate medications for their ability to reduce cue- procedure involving both visual/audio presentation induced cocaine craving, and consequently, it has been proposed as a screening mechanism for identifying po- From the Psychiatry Services NYVAMC (MSR), New York Uni- tentially therapeutic compounds for the treatment of versity Medical Center, New York, New York; and Psychiatry Ser- vices SFVAMC (JDM, KLD, SPB), University of California, San cocaine addiction (Berger et al. 1996; Robbins et al. 1992; Francisco, California. Kranzler and Bauer 1992; Satel et al. 1995). Address correspondence to: Malcolm S. Reid, Psychiatry Ser- Studies investigating the pharmacological modula- vices, NYVAMC 116A, 423 East 23rd Street, New York, NY 10010. Received February 3, 1998; revised July 20, 1998; accepted July 22, tion of cue-induced cocaine craving have tested a wide 1998. variety of compounds. These include bromocriptine

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00076-1

298 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3

(Kranzler and Bauer 1992), (Robbins et al. done over the phone, followed by a screening interview 1992), haloperidol (Berger et al. 1996) and nicotine (Reid at the SFVAMC with a SAT trained psychology techni- et al. 1998), as well as tryptophan depletion, which re- cian with experience in cocaine abuse diagnosis and duces serotonin levels (Satel et al. 1995). Most of these treatment. Patients were included if they were: (1) studies found either a reduction (haloperidol, tryp- males or nonpregnant/nursing females, (2) 18–65 years tophan depletion) or no change (bromocriptine, aman- of age, (3) regular (10 cigarettes/day) cigarette smokers, tadine) in self-reported cocaine craving and have led to (4) “crack” cocaine was their of choice, (5) had the suggestion that dopamine may be involved in medi- smoked “crack” cocaine within the last 3 months and ating cocaine craving (Berger et al. 1996; Wickelgren (6) cocaine-dependent within the last 3 months accord- 1997). More recently, we found that nicotine produced ing to DSM-IV criteria from the Structural Clinical In- an increase in cue-induced cocaine craving (Reid et al. terview (SCID). Patient were excluded if they were: (1) 1998). This findings is consistent with previous investi- currently abusing opiates or in a mainte- gations of cocaine–nicotine interactions. Thus, epidemi- nance program, (2) had undergone or drug ological studies have reported that cigarette smoking is detoxification within the last 30 days, (3) taking pre- significantly more prevalent in cocaine-dependent indi- scribed psychoactive medication, (4) taking prescribed viduals (Budney et al. 1993; Sees and Clark 1991), that antibiotics, (5) had coronary heart disease or high blood cocaine-dependent smokers reported an earlier age of pressure, or (6) had previously suffered from a serious onset and more frequent use of cocaine than cocaine- head injury (trauma) or stroke. The psychiatric status of dependent nonsmokers (Budney et al. 1993) and that all patients was initially evaluated by a Master’s degree smoking is predictive of the abuse of psychoactive level SAT psychologist. Those with erratic behavior such as cocaine (Henningfield et al. 1990; U.S. De- were interviewed by an SAT psychiatrist, and if they partment of Health and Human Services 1988). Indeed, met criteria for an axis I psychiatric disorder (other than anecdotal reports by patients claim that smoking men- substance abuse), they were excluded from the study. tholated cigarettes prolongs the cocaine high and can Following the screening interview, written informed even substitute for cocaine during periods of abstinence consent was obtained, and all study participants under- (Sees and Clark 1991). Finally, animal studies have went an intake assessment including a demographic shown that subchronic pretreatment with nicotine in- questionnaire, the drug and alcohol sections of SCID for creases the subsequent acquisition and rate of cocaine DSM-IV (First et al. 1996), the Addiction Severity Index self-administration in rats (Horger et al. 1992). These (ASI) (McLellan et al. 1980), the Fagerström Nicotine studies indicate that nicotine could stimulate the use of Tolerance Questionnaire (Fagerström 1978) and the cocaine and possibly increase the risk of relapse in co- Profile of Mood States (POMS) (McNair et al. 1971), and caine-dependent individuals during rehabilitation. More- test dates for two separate sessions (at least 72 h apart) over, this suggests that a nicotine antagonist could reduce were scheduled. cue-induced cocaine craving and, consequently, could Descriptive data of the patient population derived be of therapeutic value in the treatment of cocaine addic- from the screening interview, ASI, POMS, and Fager- tion. Mecamylamine is a clinically available, centrally ström Nicotine Tolerance Questionnaire are shown in active nicotine antagonist with known therapeutic value Table 1. All patients abused cocaine by smoking in ; it reduces relapse in cigarette “crack” cocaine, 14 of them had used within the last 30 smokers when combined with nicotine patch treatment days, 10 were currently in the SAT outpatient program, (Rose et al. 1994). Therefore, in the present study, we and all were current cigarette smokers. have investigated the effects of mecamylamine on cue- induced cocaine craving in cocaine-dependent “crack” Study Design: Methodological Considerations smokers. All patients were instructed to abstain from smoking from midnight before each test day. (Studies began at METHODS 9:30 A.M. and were completed by approximately 1:30 P.M.) Compliance was verified on each test day using a Participants carbon monoxide (CO) breath monitor (15 PPM cut-off This human study was approved by an independent, level). All patients were also instructed to abstain form University of California research council: Committee on cocaine use for at least 2 days before each test day, Human Research. Individuals were recruited from the which was verified with qualitative urine screens for transition group at the Substance Abuse Treatment cocaine (300 ng/ml cut-off). (SAT) clinic at the San Francisco Veterans Affairs Medi- Mecamylamine (2.5 mg tablet, Merck) or placebo cal Center (SFVAMC), as well as by word of mouth at (lactose tablet) were administered in gelcaps in a dou- other outpatient treatment clinics in the San Francisco ble-blind, randomized, counterbalanced design. All pa- metropolitan area. Initial contact and recruitment were tients served in all conditions resulting in a within-patient

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 299

Table 1. Subject Demographics and Drug Use History

Frequency Mean (SD)

Demographics Race African American 19 Caucasian 4 Gender Male 20 Female 3 Age 40.6 (5.1) Income in last 30 days ($) Employment 82 (159) All 833 (1854) Years of education 13.2 (1.3) Self reported drug and alcohol use Number of days of drug use in last 30 days Cocaine 8.8 (9.1) Alcohol 5.1 (9.4) Cannabis 2.4 (6.4) Amphetamine 0 (0) Number of days since last cocaine use 28.5 Money spent in last 30 days ($) Alcohol 10 (19) Drugs 237 (430) Years lifetime use Cocaine 12.3 (7.0) Alcohol 15.1 (10.4) Cannabis 11.8 (9.6) Amphetamine 2.6 (5.5) Nicotine use Cigarettes/day 15.6 (7.4) Number of attempts to quit smoking 2.3 (1.8) Addiction scores Fagerström Nicotine Tolerance Total 6.5 (2.0) ASI Drug Composite 0.17 (0.13) POMS Total Mood Disturbance 47.9 (47.5)

Lifetime drug use defined as Addiction Severity Index (ASI) criterion for 3 or more times a week for at least 1 month. Means and standard deviation (SD) are reported. The ASI (Drug) Composite scores were calculated using drug-related measures as described by McLellan and colleagues (1980), the Nicotine Tolerance (Total) scores were calculated using the sum of derived nicotine related measures as described by Fagerström (1978) and the Profile of Mood States (POMS) Total Mood Disturbance scores were calculated according to McNair and colleagues (1971). study design. Randomization of treatment schedule by the patient’s nonwriting hand. Both measurements block (4ϫ) permutation ensured that a roughly equal were recorded continuously. For the first baseline psy- number of patients received mecamylamine or placebo chological measurements, the patient was given the on the first day of testing (to control for cue novelty ef- Within Sessions Rating Scale and the Mood Analog fects). The dose of mecamylamine was chosen to mini- Scale immediately before cue presentation. Thereafter, mize its peripheral side effects and because of its contri- each individual was shown a 5-min neutral cue video- bution to any possible withdrawal. tape followed by the handling of neutral cues for 5 to 7 min. After completion of the video and handling of the neutral cues, the Within Sessions Rating Scale and the Mood Analog Scale were administered again. Once Study Design: Test Procedures completed, the physiological recordings were stopped A time-line descriptive schemata of the procedures for and the patient was administered mecamylamine (2.5 Day 1 and Day 2 can be seen in Figure 1. Both days of mg) or placebo. After a 2-h medication absorption pe- testing took place in the SFVAMC Psychiatry Services riod, a procedure similar to the neutral cue presentation Inpatient Unit clinical research laboratory. Upon the be- was followed, except that patients were exposed to a ginning of each test session, skin conductance, skin 5-min videotape containing cues specific to crack cocaine temperature and heart rate electrodes were attached to and were instructed to handle cocaine and crack related

300 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3

Figure 1. Cue-induced cocaine craving study design summary. Each test day lasted approxi- mately 4 h (9:30 A.M.–1:30 P.M.). Test days 1 and 2 were at least 72 h apart.

paraphernalia for 5 to 7 min after viewing the video- Within Session Rating Scale, tobacco withdrawal, was tape. As previously described, skin conductance, skin used to test for effects of medication alone. Of these five temperature and heart rate were recorded continu- measures, three (cocaine craving, anxiety, tobacco with- ously, and the Within Sessions Rating Scale and the drawal) were derived by averaging more than one indi- Mood Analog Scale were administered immediately be- vidual item and two (cocaine-like high, desire to use co- fore and after cocaine cue presentation. caine now) were derived from a single item on the On Day 2, all individuals were tested in a counterbal- visual analog scales. Of the indexed items, cocaine crav- anced format: Patients who received mecamylamine on ing was obtained by averaging the scores of four co- Day 1 received placebo and vice versa. The testing pro- caine craving questions, anxiety was obtained by aver- cedure was identical to that of Day 1, except the video aging the scores of three anxiety-related questions, and contained a different cocaine-related scene. Following tobacco withdrawal was obtained by averaging the scores completion of Day 2, all patients were asked, in a dou- of two smoking-related questions. One of the individ- ble-blind setting, which day (Day 1 or Day 2) they felt ual items, desire to use cocaine now, was analyzed to the most cocaine craving. Patients were then paid for assure comparability with previous research (Robbins their study participation. et al. 1992; Kranzler and Bauer 1992; Satel et al. 1995; Berger et al. 1996). Subjective Measures Physiological Measures Drug craving was rated on a recent version of the Within Session Rating Scale developed by Childress Skin conductance (␮MHOS), skin temperature (CЊ) and and colleagues (Childress et al. 1986), whereas mood was heart rate (bpm) were recorded at a 2 Hz frequency us- measured using the Mood Analog Scale (Berger et al. ing fingertip electrodes connected to a laptop PC via a 1996). The Within Session Rating Scale is a self-reported RS232 beltpack/interface unit (ProComp, Thought measure in which patients estimate the intensity of their Technology, Montreal, Canada). Skin conductance was current desire and likelihood to use cocaine, cocaine- recorded using Ag-Ag/Cl paste electrodes, skin tem- like high, desire to use tobacco, tobacco withdrawal, perature was recorded using an electric thermister, and and a variety of drug-related states on a 1- to 100-mm heart rate was recorded using a photoelectric pulse sen- visual analog scale. The Mood Analog Scale contains 16 sor (for more detail see Reid et al. 1998). adjectives describing the patient’s current feelings that are rated on a similar 1- to 100-mm visual analog scale. Cocaine Cues The anxiety related adjectives: “nervous,” “anxious,” and “irritated” were chosen for analysis based on previ- The 5-min cocaine cue video tape contained scenes per- ous studies of cue-induced cocaine craving (for more formed by actors simulating the purchase and smoking detail see Reid et al. 1998). of “crack” cocaine, which were interspliced with video The primary outcome measures from the Within Ses- clips of actual crack smoking (provided by Childress sion Rating Scale and Mood Analog Scale were cocaine and colleagues). In the subsequent 5 to 7 min, patients craving, desire to use cocaine now, anxiety, and co- handled cocaine and crack paraphernalia, including caine-like high. A secondary outcome measure from the various crack pipes, screens, lighters, and a benzocaine-

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 301

derived white crystalline powder designed to simulate first day of testing (day effect: F(1,13) ϭ 14.22, p ϭ .002). crack “rocks,” and were asked to smell a recently used The effects of medication alone were tested by compar- pipe for any scent of crack residue (reapplied every ing baseline with precocaine cue Within Session Rating month using pseudo-cocaine); patients were then in- Scales and Mood Analog Scales; the analyses are pre- structed to prepare a pipe of their choice for smoking sented in Table 2. An overall decrease in cocaine crav- crack (mock ritual). ing, desire to use cocaine now and anxiety, was found across time (time effect), but this did not differ by drug condition (time ϫ drug effect). In contrast, no overall Neutral Cues changes in cocaine-like high or tobacco withdrawal The 5-min neutral cue video tape consisted of images of were found across time (time effect), though compari- pine cones and seashells. In the subsequent 5 to 7 min, son between mecamylamine and placebo conditions re- patients handled shells, rocks, and a pine cone, were vealed a moderate drug-induced drop in tobacco with- asked to smell a fragrant spice (nutmeg), and were in- drawal (time ϫ drug effect). The mean values and structed to make 2 to 3 patterns on the desk top with the standard deviation for each of the outcome measures at items. the baseline and precocaine cue time points of the pro- tocol, showing the effects of mecamylamine or placebo, are shown in Figure 2a–e. Data Analysis Each patient was also asked to guess whether he/she Mean levels of the subjective outcome measures were had received mecamylamine or placebo on each testing compared for statistical significance using a 2 (pre-cue, day (part of the Within Sessions Rating Scale). Tests of post-cue)-by-2 (mecamylamine, placebo) repeated mea- proportion using a McNemar’s chi-squared statistic on sures ANOVA model. All of these models were ana- precocaine cue answers revealed that they were unable lyzed after initially testing for cue reactivity order ef- to detect which medication they had received on Day 1 fects and, except for anxiety (drug ϫ time interaction: (chi-squared ϭ 0.000, df ϭ 1, p ϭ 1.000) or Day 2 (chi- F(1,21) ϭ 4.90, p ϭ .038), none were found. Because the squared ϭ 1.333, df ϭ 1, p ϭ .248). neutral cue presentation, the effects of medication alone, and cocaine cue presentation addressed separate research questions their data were analyzed separately. Subjective Measures: Cue-Induced Cocaine Baseline and cue-induced levels of skin conductance, Craving Tests skin temperature, and heart rate were analyzed using using a 2 (mecamylamine, placebo) ϫ 3 (baseline, video The effects of mecamylamine on cue-induced changes viewing, paraphernalia handling) ϫ 10 (time points/ in subjective measures were tested by comparing pre- stimulus phase) repeated measures ANOVA model. and postcocaine cue scores from the Within Sessions Each time point was calculated as the mean of a 30 s re- cording period. As a secondary analysis, correlation co- efficients were estimated to measure the relationship Table 2. ANOVA F and p Value for Drug, Time, and between cue-induced cocaine craving and (1) cue-induced Drug ϫ Time Effects of Baseline to Precocaine Cue Changes anxiety, (2) the number of days since last cocaine use, on Subjective Outcome Measures (3) current enrollment in a cocaine abuse rehabilitation program, (4) ASI Drug Composite, (5) Fagerström Nico- Factor F d.f. p tine Tolerance, and (6) POMS Total Mood Disturbance Cocaine craving Drug 0.07 1,22 .807 (TMD) scores. Proportion of patients correctly guessing Time 21.3 1,22 .001 which medication was received was tested for differ- Drug ϫ Time 0.25 1,22 .621 ence from a chance level of 50%. Desire to use cocaine now Drug 0.04 1,22 .836 Time 7.13 1,22 .014 Drug ϫ Time 0.65 1,22 .428 Anxiety Drug 0.07 1,22 .794 RESULTS Time 5.18 1,22 .033 Drug ϫ Time 0.02 1,22 .893 Subjective Measures: Control Tests Cocaine-like high Drug 0.00 1,22 .962 Time 0.26 1,22 .612 Neutral cues were tested on all patients before receiv- Drug ϫ Time 0.18 1,22 .677 ing medication. Comparison of pre- and postneutral Tobacco withdrawal Drug 1.72 1,22 .203 cue Within Session Rating Scales and Mood Analog Time 2.85 1,22 .105 Scales revealed no significant changes in cocaine crav- Drug ϫ Time 6.33 1,22 .020 ing, desire to use cocaine now, cocaine-like high, anxi- Statistical analyses of the change in each subjective outcome measure ety and tobacco withdrawal over time (time effect), during the medication treatment phase of testing (baseline to pre-cue though the overall levels of craving were higher on the testing).

302 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3

Figure 2. Baseline and postmedication (precocaine cue) levels of the subjective outcome measures from the visual analog scales. Means and standard deviations (measured in mm) are presented. In (e), asterisk indicates p Ͻ .05 for comparison of precue mecamy- lamine with Baseline mecamylamine values.

Rating Scales and the Mood Rating Scales; the analyses tions, are shown in Figure 3. Kendall Tau correlations are presented in Table 3. Consistent with our previous revealed a negative relationship between cue-induced studies (Berger et al. 1996; Reid et al. 1998), exposure to cocaine craving and the number of days since last cocaine cocaine-related cues resulted in a significant increase in use during the placebo (␶ ϭ Ϫ0.417, p ϭ .048) but not all primary outcome measures during both mecamy- the mecamylamine (␶ ϭ 0.114, p ϭ .604) condition. All lamine and placebo conditions (time effect). Compari- other correlation analyses between cue-induced cocaine son of the increase in each measure across condition craving and cue-induced anxiety, cocaine abuse treat- (time ϫ drug effect) revealed that cue-induced cocaine ment status, ASI, Fagerström Nicotine Tolerance, or craving and desire to use cocaine now were signifi- POMS TMD scores did not reveal any significant associ- cantly lower during the mecamylamine condition. Cue- ation during either condition. Following completion of induced anxiety and cocaine-like high were unaffected the last day of testing (Day 2), patients were asked dur- by mecamylamine treatment (time ϫ drug effect). The ing which day (Day 1 or Day 2) they felt the highest mean values and standard deviation for the cocaine level of cocaine craving following cue exposure. A ma- cue-induced change in each of the primary outcome jority of the subjects (77%) reported that they felt more measures, during mecamylamine and placebo condi- craving during the placebo than mecamylamine condi-

NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 303

Table 3. ANOVA F and p Values for Drug, Time, and (time effect) and, though it appeared that mecamy- Drug ϫ Time Effects of Pre- to Postcocaine Cue Changes on lamine produced moderate reduction in baseline con- Subjective Outcome Measures ductance and increase in baseline temperature, did not differ by drug condition (drug effect) (Table 5). Follow- Factor F d.f. p ing exposure to cocaine cues there was a significant in- Cocaine craving Drug 0.51 1,22 .444 crease in skin conductance and decrease in skin temper- Time 33.9 1,22 .001 ϫ ature but no change in heart rate over time (time effect) Drug Time 4.73 1,22 .041 in which each phase of cue presentation (baseline, Desire to use cocaine now Drug 2.25 1,22 .148 Time 39.2 1,22 .001 video, handling) elicited an incrementally greater re- Drug ϫ Time 6.30 1,22 .020 sponse (phase effect). However, comparison of the cue- Anxiety Drug 0.97 1,22 .336 induced changes in skin conductance, skin tempera- Time 7.04 1,22 .015 ϫ ture, and heart rate revealed no significant differences Drug Time 1.55 1,22 .227 between mecamylamine and placebo conditions (drug Cocaine-like high Drug 0.13 1,22 .727 ϫ ϫ ϫ ϫ Time 32.6 1,22 .001 time, drug phase, and drug time phase ef- Drug ϫ Time 0.95 1,22 .340 fects) (Table 6).

Statistical analyses of the change in each of the primary subjective out- come measures following exposure to cocaine cues (pre- to post-cocaine cue testing). DISCUSSION

The main finding from this study is that treatment with a Ͻ tion, which was significantly different (p .05) from a nicotine antagonist, mecamylamine, reduces cue-induced chance level of 50% in a binomial test of proportion. cocaine craving in cocaine-dependent subjects. In addi- tion, mecamylamine also produced a moderate reduc- Physiological Measures tion in tobacco withdrawal before cocaine cue testing. Precocaine cue levels of cocaine craving, however, were Skin conductance, skin temperature, and heart rate re- not affected by mecamylamine. These findings extend cordings were successfully obtained in 16 of 23 patients our previous work on the effects of transdermal nico- studied. The mean recordings of skin conductance and tine patches (Reid et al. 1998) by further demonstrating skin temperature are shown (Figure 4a,b) however, due the ability of nicotinergic drugs to modulate conditioned to considerable variability in the heart rate recordings cocaine craving. Indeed, the opposing effects of a nico- these data are presented as mean values for each phase tinic and antagonist indicate the involvement of of cue presentation (Table 4). Statistical analysis of the a specific receptor site in the CNS. physiological recordings are presented in Tables 5 and All patients were instructed to abstain from smoking 6. Baseline measures of skin conductance, skin tempera- cigarettes for 12 to 14 hr before being tested, which ture and heart rate were stable before cue exposure might result in a moderate level of distress and tobacco withdrawal before cocaine cue testing. In addition, the administration of a might possibly exacerbate this condition, based on previous studies showing that mecamylamine produces an increase in the rate of smoking and self-administered nicotine dose level (Nemeth-Coslett et al. 1986; Rose et al. 1989). However, although mecamylamine may reduce the level of satisfaction obtained from cigarette smoking (Rose et al. 1994), it is not clear that mecamylamine will induce withdrawal symptoms per se (Eissenberg et al. 1996) or even attenuate the withdrawal-alleviating effects of subsequent smoking (Rose et al. 1994). We found that mecamylamine treatment actually reduced the levels of self-reported tobacco withdrawal, even though patients were unable to detect when they received active medi- Figure 3. Cue-induced changes (pre- to postcocaine cue cation. All other subjective measures, including anxiety, testing) in the primary outcome subjective measures from had similar baseline levels and were unaffected by the visual analog scales measured in mm. Means and stan- mecamylamine treatment. The drop in tobacco with- dard deviations are presented; asterisks indicate p Ͻ .05 for drawal may be reflective of the low dose of mecamy- comparison of mecamylamine with placebo. lamine used in this study because others have reported 304 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3

Figure 4. Physiological mea- sures of (a) skin conductance and (b) skin temperature on each test day. The means across all patients (n ϭ 16) were calcu- lated at each recording time. In (a), the units of skin conduc- tance are expressed as ␮MHOS [conductance (MHO) is inverse of the resistance (OHM)] and in (b), the units of skin tempera- ture are expressed in ЊC.

that low doses (2.5–10 mg) of mecamylamine produce a Though the overall ratings of cocaine craving tended decrease in the desire to smoke (Rose et al. 1989). Previ- to be higher on the first day of testing these, as well as ous studies on smoking cessation found that co-admin- the other subjective measures, were unaffected by neu- istration of mecamylamine (2.5–5 mg/kg/day) with tral cues. This lack of neutral cue effects is consistent nicotine transdermal patches improved the rate of ab- with previous cue reactivity studies (Ehrman et al. stinence in smokers, and it was suggested that mecamy- 1992). The reduction in cocaine craving from Day 1 to lamine reduced cigarette craving whereas nicotine at- Day 2 might be attributed to patient habituation to the tenuated withdrawal symptoms (Rose et al. 1994). Our testing procedure and is consistent with previous stud- findings on baseline levels of tobacco-related with- ies reporting a decline in baseline levels of desire for co- drawal are consistent with this hypothesis. caine and cocaine-like euphoria from Session 1 to Ses- NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 305

Table 4. Heart Rate Levels (bpm) During Cocaine Cue Table 6. ANOVA F and p Values for Drug, Time, and Presentation (n ϭ 16) Phase (Including Factor Interaction) Effects on Skin Conductance, Skin Temperature, and Heart Rate Before and Placebo Mecamylamine During Cocaine Cue Exposure

Baseline 70.6 (12.0) 72.7 (10.1) Factor F d.f. p Video viewing 70.2 (15.8) 70.9 (11.9) Paraphernalia handling 69.8 (16.2) 71.0 (11.4) Conductance Drug 2.12 1,15 .166 Time 3.96 9,135 .001 Heart rate levels during baseline, video viewing, and paraphernalia Phase 5.89 2,30 .007 handling phases of cocaine cue presentation. Mean and standard devia- Drug ϫ Time 0.23 9,135 .989 tion (SD) of beats per minute (bpm) are reported. Drug ϫ Phase 0.02 2,30 .985 Time ϫ Phase 5.76 18,270 .001 Drug ϫ Time ϫ Phase 0.25 18,270 .999 sion 2 (Kranzler and Bauer 1992; Robbins et al. 1992). Temperature Drug 0.20 1,15 .660 Though a reduction in baseline cocaine craving be- Time 20.4 9,135 .001 Phase 22.1 2,30 .001 tween days could arguably influence the outcome of the Drug ϫ Time 0.10 9,135 .999 cue-induced cocaine craving tests, statistical analysis re- Drug ϫ Phase 0.33 2,30 .719 vealed no order effects on this and the other subjective Time ϫ Phase 4.30 18,270 .001 measures (except for anxiety). Drug ϫ Time ϫ Phase 0.46 18,270 .973 Cue-induced increases in cocaine craving and desire Heart Rate Drug 0.03 1,15 .875 Time 0.52 9,135 .861 to use cocaine now were significantly reduced by Phase 0.61 2,30 .550 mecamylamine. The increase in each of these measures Drug ϫ Time 0.20 9,135 .918 was reduced by approximately 50% during the active Drug ϫ Phase 0.36 2,30 .702 day. The concordance between these two craving re- Time ϫ Phase 0.38 18,270 .991 ϫ ϫ lated measures indicates the robust effect of mecamy- Drug Time Phase 0.51 18,270 .952 lamine and further supports our contention that the in- Statistical analyses of the change in skin conductance, skin tempera- dividual cocaine craving related questions in the Within ture and heart rate following exposure to cocaine cues (baseline, video Sessions Visual Analog Scale are highly correlated (see viewing and paraphernalia handling time points). also Reid et al. 1998; Berger et al. 1996). In addition, a significant majority of patients reported more craving on the placebo day when asked to compare both days of otinergic compounds selectively modulate craving re- testing. Although the measures for cocaine craving sponses in cocaine-dependent patients. In contrast, the were found to be reduced, cue-induced cocaine-like ability of haloperidol to reduce both cue-induced co- high was not altered by mecamylamine treatment. This caine craving, anxiety, and cocaine-like high (Berger et is an important distinction and suggests that these re- al. 1996) suggests that dopaminergic compounds pro- lated cocaine-conditioned responses are not similarly duce a more generalized effect on cocaine-conditioned regulated. Similar findings were obtained in our previ- responses. Consistent with this latter suggestion, Rob- ous study on nicotine—modulation of the craving but bins and colleagues (1992) found that amantadine en- not cocaine-like high responses (Reid et al. 1998). To- hanced the arousal response—increases in heart rate gether, these findings support the suggestion that nic- and skin resistance—to cocaine cues. It must be ac- knowledged, however, that the selective cocaine crav- ing modulatory effects of nicotine and mecamylamine Table 5. ANOVA F and p Values for Drug, Time, and Drug in our studies may have been influenced by the fact that ϫ Time Effects During Baseline Skin Conductance, Skin all subjects were also cigarette smokers. Temperature, and Heart Rate Recording Correlation analyses found a significant, negative correlation between cue-induced cocaine craving and Factor F d.f. p the number of days since last cocaine use during the Conductance Drug 2.88 1,15 .110 placebo condition. This indicates that the cocaine crav- Time 1.00 9,135 .445 ing response was stronger in patients who had abused ϫ Drug Time 0.12 9,135 .999 cocaine more recently, and may be reflective of the cur- Temperature Drug 0.11 1,15 .745 Time 0.99 9,135 .452 rent users (versus individuals in rehabilitation pro- Drug ϫ Time 0.43 9,135 .915 grams) in our subject population. Although it would be Heart rate Drug 0.13 1,15 .719 speculative to draw any conclusions from this finding, Time 1.11 9,135 .361 our previous study also found a correlation between ϫ Drug Time 0.55 9,135 .836 cue-induced cocaine craving and the number of days Statistical analyses of baseline skin conductance, skin temperature and since last cocaine use, but this was a positive correlation heart rate before cocaine cue exposure. and occurred during the nicotine condition (Reid et al. 306 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3

1998). Therefore, it is suggested that the duration of co- 1994) suggests that it is an effective anti-craving agent. caine abstinence before testing could significantly influ- The findings that smokers spontaneously decrease their ence cue-induced cocaine craving, and, consequently, smoking habits when receiving mecamylamine, even future cocaine cue reactivity studies should take this before they begin the smoking cessation treatment (Rose into account. et al. 1994), suggests that it may also induce a form of Cue-induced anxiety was not significantly affected reward extinction. Our findings with cue-induced cocaine by mecamylamine treatment, although a moderate de- craving indicate that these effects might also apply to crease was seen. Our previous study indicated that nic- cocaine addiction processes. Further studies on the psy- otine increases cue-induced anxiety (Reid et al. 1998) chopharmacological effects of mecamylamine in co- and, though caution should be taken when comparing caine-dependent subjects, including treatment trials for data from different studies, the levels of anxiety seen cocaine addiction, are needed to address these questions. during mecamylamine were less than 50% of those seen during nicotine. This difference supports the suggestion that nicotinergic drugs do in fact modulate cue-induced ACKNOWLEDGMENTS anxiety. However, it cannot be ruled out that the anxi- ety measures were affected by other factors besides This study was supported by NIDA grant 1R18DA06097 drug or cocaine cue exposure, and it is quite possible (MSR) and NIDA/VA grant YOIDA50038-00 (SPB). that nicotinergic drugs could have different effects in cocaine-dependent, nonsmokers. Cocaine cues produced a significant increase in skin REFERENCES conductance and decrease in skin temperature, whereas heart rate remained unchanged. Similar to ours and Berger SP, Hall SM, Mickalian JD, Reid MS, Crawford CA, other earlier studies (O’Brien et al. 1990; Reid et al. Delucchi KL, Carr K, Hall S (1996): Haloperidol antago- nism of cue-elicited cocaine craving. Lancet 347:504–508 1998), the changes in conductance and temperature were greatest at the end of the cue exposure protocol, Budney AJ, Higgins ST, Hughes JR, Bickel WK (1993): Nico- tine and caffeine use in cocaine-dependent individuals. during the paraphernalia handling phase. Previous J Subst Abuse 5:117–130 studies have found similar skin conductance and tem- Childress AR, McLellan AT, O’Brien CP (1986): Conditioned perature results; however, they also reported a signifi- responses in a methadone population: A comparison of cant increase in heart rate following exposure to cocaine laboratory, clinic and natural setting. J Subst Abuse cues (Ehrman et al. 1992; Kranzler and Bauer 1992; Rob- Treat 3:173–179 bins et al. 1992). This discrepancy is likely be due to the Ehrman RN, Robbins SJ, Childress AR, O’Brien CP (1992): high variability of heart rate recordings obtained from Conditioned responses to cocaine-related stimuli in the fingertip photoelectric pulse sensors used in the cocaine abuse patients. Psychopharmacol 107:523–529 present study. Comparisons based on drug condition Eissenberg T, Griffiths RR, Stitzer ML (1996): Mecamylamine did not reveal any significant effects of mecamylamine does not precipitate withdrawal in cigarette smokers. on basal or cue-induced changes in skin conductance or Psychopharm 127:328–336 temperature. However, visual analysis suggested a mi- Fagerström KO (1978): Measuring degree of physical depen- nor increase in baseline skin temperature and decrease dence to tobacco smoking with reference to individual- ization of treatment. Addictive Behav 3:235–241 in baseline skin conductance following mecamylamine. This difference would be consistent with the peripheral, First MB, Spitzer RL, Gibbon M, Williams JBW (1996): Struc- tured Clinical Interview for DSM-IV Axis I Disorders— hypotensive and ganglionic blocking effects of Patient Edition (SCID-I/P, Version 2.0), Biometrics mecamylamine (see Eissenberg et al. 1996). Further- Research Department, New York State Psychiatric Insti- more, such drug effects could attenuate the dynamics of tute, New York skin temperature and conductance responses to cocaine Henningfield JE, Clayton R, Pollin W (1990): Involvement of cue exposure. tobacco in alcoholism and illicit drug use. Brit J Addict The present finding that mecamylamine reduces cue- 85:279–292 induced cocaine craving in cocaine-dependent patients Horger BA, Giles MK, Schenk S (1992): Preexposure to suggests that mecamylamine might be a useful tool in amphetamine and nicotine predisposes rats to self- relapse prevention programs. It should be noted, how- administer a low dose of cocaine. Psychopharmacol 107:271–276 ever, that these studies were limited to cocaine-depen- dent subjects who are also cigarette smokers. In terms Kranzler HR, Bauer LO (1992): Bromocriptine and cocaine cue reactivity in cocaine-dependent patients. Brit J of addiction treatment, it is already known that Addict 87:1537–1548 mecamylamine is of therapeutic value in smoking ces- McLellan AT, Luborsky L, O’Brien CP, Woody GE (1980): sation (Rose et al. 1994). The ability of low doses to re- An improved evaluation instrument for substance duce the desire to smoke and the satisfaction derived abuse patients: The Addiction Severity Index. J Nervous from smoking (Nemeth-Coslett et al. 1986; Rose et al. Mental Disease 168:26–33 NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 307

McNair DM, Lorr M, Droppelman LF (1971): Manual: Profile retical and treatment implications. Int J Addict 25:975– of Mood States, San Diego, California, Educational and 993 Industrial Testing Service Rose JE, Behm FM, Westman EC, Levin ED, Stein RM, Ripka Nemeth-Coslett R, Henningfield JE, O’Keefe MK, Griffiths GV (1994): Mecamylamine combined with nicotine skin RR (1986): Effects of mecamylamine on human cigarette patches facilitates smoking cessation beyond nicotine smoking and subjective ratings. Psychopharm 88:420– patch treatment alone. Clin Pharmacol Therapeutics 425 56:86–99 O’Brien CP, Childress AR, McLellan T, Ehrman R (1990): Rose JE, Sampson A, Levin ED, Henningfield JE (1989): Integrating systemic cue exposure with standard treat- Mecamylamine increases nicotine preference and atten- ment in recovering drug dependent patients. Addictive nuates nicotine discrimination. Pharmacol Biocem Behav Behav 15:355–365 32:933–938 O’Brien CP, Childress AR, McLellan AT, Ehrman R (1992): Satel SL, Krystal JH, Delgado PL, Kosten TR, Charney DS Classical conditioning in drug-dependent humans. (1995): Tryptophan depletion and attenuation of cue- Annal NY Acad Sci 654:400–415 induced craving for cocaine. Am J Psychiatry 152:778–783 Reid MS, Mickalian JD, Delucchi KL, Hall SM, Berger SP Sees KL, Clark HW (1991): Substance abusers want to stop (1998): An acute dose of nicotine enhances cue-induced smoking! Alcohol: Clin Experiment Res 15:152 cocaine craving. Drug Alcohol Depend 49:95–104 U.S. Department of Health and Human Services (1988): The Robbins SJ, Ehrman RN, Childress AR, O’Brien CP (1992): health consequences of smoking: Nicotine addiction: A Using cue reactivity to screen medications for cocaine report of the Surgeon General, (DHHS Publication No. abuse: a test of amantadine hydrochloride. Addict CDC 8-8406), Washington, D.C., U.S. Government Print- Behav 17:491–9 ing Office Rohsenow DJ, Niara RS, Childress AR, Abrams DB, Monti Wickelgren I (1997): Getting the brain’s attention. Science PM (1991): Cue reactivity in addictive behaviors: theo- 278:35–37